8-alkylaminoimidazo(1,2-a)pyrazines and derivatives, their preparation and their application in therapy

Abstract

PCT No. PCT/EP87/00756 Sec. 371 Date Jun. 2, 1989 Sec. 102(e) Date Jun. 2, 1989 PCT Filed Dec. 4, 1987 PCT Pub. No. WO88/04298 PCT Pub. Date Jun. 16, 1988. <IMAGE> (I) Novel 8-alkylamino-imidazo(1,2-a)pyrazines of formula (I) show advantages pharmacological activities. They can be used for medical products in human and veterinary therapy in the field of applications of antispasmodics, uterine relaxants, bronchodilators, cardiac analeptics and neurosedatives.

We claim: 
     
       1. An 8-aminoimidazo[1,2-a]pyrazine compound corresponding to formula (I) or a salt which is compatible with pharmaceutical application, which corresponds to the formula: ##STR17## in which formula: . Y and Z independently denote: a) a hydrogen atom,   b) F, Cl, Br or I,   c) CO 2  H,   d) CN,   e) a linear or branched C 1  -C 5  alkyl radical,   f) a C 1  -C 5  alkoxy radical,   g) CF 3  ##STR18##  with R 3  and R 4  as defined below; . R 1  and R 2 , when they are independent, denote,   a) a hydrogen atom,   b) F, Cl, Br or I,   c) a linear or branched C 1  -C 5  alkyl radical,   d) a radical --(CH 2 ) n  --CO 2  R 5 , with R 5  denoting a C 1  -C 5  alkyl radical and n being from 0 to 4, ##STR19##  with R 6  and R 7  independently denoting a hydrogen atom, a linear or branched C 1  -C 5  alkyl radical or an aryl radical,   f) CN, ##STR20## h) NH 2 , i) CH 2  Cl,   j) CH 2  OH,   k) CF 3 , ##STR21## m) --NO 2 , n) --NO,   o) a C 3  -C 6  cycloalkyl radical,   p) a linear or branched C 1  -C 5  alkylthio radical;     R 1  and R 2 , when they are linked to one another, denote --CH 2  --CH 2  --CH 2  --CH 2  --,     R 3  and R 4  independently denote: a) a hydrogen atom   b) a linear or branched C 1  -C 5  alkyl radical, capable of bearing one or more halogen atoms or a hydroxy, N(C 1  -C 4  alkyl)2, carbamoyl or C 1  -C 4  alkoxy radical, either a C 3  -C 6  cycloalkyl radical or a phenyl radical,   c) a furfuryl radical,       R 3  and R 4 , linked to one another denote --CH 2  --CH 2  --CH 2  --CH 2  --CH 2  or --CH 2  --CH 2  --X--CH 2  --CH 2  -- in which X denotes O or S.   
     
     
       2. A compound as claimed in claim 1, which corresponds to the formula (I) in which R 3  ═H, R 4  ═H or a methyl or ethyl radical, R 1  ═H or an ethyl carboxylate group, Y and Z denote either H or Br and R 2  denotes Br or H. 
     
     
       3. A compound as claimed in claim 1, which corresponds to the formula (I) in which R3═H, R 4  ═CH 3  or C 2  H 5 , Y═H, Z═H, R 2  ═Br and R 1  ═H, namely, a compound of one of the formula: ##STR22## having, respectively, a melting point of 143° C. and 82° C. 
     
     
       4. A compound as claimed in claim 1, which corresponds to the formula (I) in which Y denotes a bromine atom and R 1 , R 2 , R 3 , R 4  and Z denote hydrogen atoms, namely the compound of the formula ##STR23## having a melting point of 210° C. 
     
     
       5. A compound as claimed in claim 1, which corresponds to formula (I) in which R 3  ═H, R 4  ═CH 3  or C 2  H 5 , Y═Br, Z═H, R 2  ═H, and R 1  ═H, namely: a compound of one of the formulae: ##STR24## having, respectively, a melting point of 162° C. and 99° C. 
     
     
       6. A compound as claimed in claim 1, which corresponds to formula (I) in which R 3  ═H, R 4  ═H, Y═Br, Z═H, R 2  ═Br and R 1  ═H, namely the compound of the formula: ##STR25## having a melting point of 246° C. 
     
     
       7. A compound as claimed in claim 1, which corresponds to formula (I) in which Y, Z, R 1 , R 2 , R 3  and R 4  denote hydrogen atoms, namely: the compound of the formula: ##STR26## having a melting point of 220° C. 
     
     
       8. A compound as claimed in claim 1, which corresponds to formula (I) in which Y, Z, R 1 , R 2  and R 3  denote hydrogen atoms and R 4  denotes a methyl or ethyl radical, namely: a compound of one of the formulae: ##STR27## having, respectively, a melting point of 96° C. and 98° C. 
     
     
       9. A compound as claimed in claim 1, which corresponds to formula (I) in which Y, Z, R 1  and R 2  denote hydrogen atoms and R 3  and R 4  are linked to one another to denote a --(CH 2 ) 2  --O--(CH 2 ) 2  -- radical, namely: the compound of the formula: ##STR28## having a melting point of 127° C. 
     
     
       10. A compound as claimed in claim 1, which corresponds to formula (I) in which Y, Z, R 1 , R 3  and R 4  denote hydrogen atoms and R 2  denotes a bromine atom, namely: the compound of the formula: ##STR29## having a melting point of 239° C. 
     
     
       11. A compound as claimed in claim 1, which corresponds to formula (I) in which Y denotes a bromine atom, Z, R 1  and R 2  denote hydrogen atoms, and R 3  and R 4  are linked to one another to denote a --(CH 2 ) 2  --O--(CH 2 ) 2  -- radical, namely: the compound of the formula: ##STR30## having a melting point of 191° C. 
     
     
       12. A compound as claimed in claim 1, which corresponds to formula (I) in which Y, R 1 , R 2  and R 3  denote hydrogen atoms, Z denotes a chlorine atom and R 4  denotes a C 2  H 5  radical, namely: the compound of the formula: ##STR31## having a melting point of 94° C. 
     
     
       13. A compound as claimed in claim 1, which corresponds to formula (I) in which Y and R 2  denote bromine atoms, Z, R 1  and R 3  denote hydrogen atoms, and R 4  denotes a methyl or ethyl radical, namely: a compound of one of the formulae: ##STR32## having, respectively, a melting point of 229° C. and 131° C. 
     
     
       14. A compound as claimed in claim 1, which corresponds to formula (I) in which Y and R 2  denote bromine atoms, Z and R 1  denote hydrogen atoms and R 3  and R 4  are linked to one another to denote a --(CH 2 ) 2  --O--(CH 2 ) 2  -- radical, namely: the compound of the formula: ##STR33## having a melting point of 151° C. 
     
     
       15. A compound as claimed in claim 1, which corresponds to formula (I) in which Y, Z, R 2  and R 3   denote hydrogen atoms and R 4  is hydrogen or a --CH 3  radical or a --C 3  H 7  radical, and R 1  denotes a --CO 2  C 2  H 5  group, namely: a compound one of the formulae: ##STR34## having, respectively, a melting point of 230° C., 184° C. and 145° C. 
     
     
       16. A compound as claimed in claim 1, which corresponds to formula (I) in which Y, Z and R 2  denote hydrogen atoms, R 1  denotes --CO 2  C 2  H 5 , and R 3  and R 4  are linked to one another to denote either a --(CH 2 ) 5  -- radical or a --(CH 2 ) 2  --O--(CH 2 ) 2  -- radical, namely: a compound, respectively, of one of the formulae: ##STR35## having, respectively, a melting point of 114° C. and 155° C. 
     
     
       17. A compound as claimed in claim 1, which corresponds to formula (I), in which Y denotes a bromine atom, Z, R 3  and R 2  denote hydrogen atoms, R 1  denotes --CO 2  C 2  H 5 , and R 4  denotes either a hydrogen atom or one of the radicals --CH 3 , --C 2  H 5 , --C 3  H 7 , n--C 4  H 9 , s--C 4  H 9 , namely: the compounds, respectively, of formula: ##STR36## having, respectively, a melting point of 245° C., 234° C., 180° C., 190° C., 176° C. and 187° C. 
     
     
       18. A compound as claimed in claim 1, which corresponds to formula (I) in which Y denotes a bromine atom, Z and R 2  denote hydrogen atoms, R 1  denotes a --CO 2  C 2  H 5  group and R 3 , and R 4  are linked to one another to denote either a --(CH 2 ) 5  -radical, or a --(CH 2 ) 2  --O--(CH 2 ) 2  -radical, namely: the compounds, respectively, of the formulae: ##STR37## having, respectively, a melting point of 134° C. and 140° C. 
     
     
       19. A compound as claimed in claim 1, which corresponds to formula (I) in which Y denotes a bromine atom, Z, R 2  and R 3  denote hydrogen atoms, R 4  denotes a --(CH 2 ) 2  OH radical, and R 1  denotes a --CO 2  C 2   5  group, namely: the compound of the formula: ##STR38## having a melting point of 208° C. 
     
     
       20. A compound as claimed in claim 1, which corresponds to formula (I) in which Y denotes a bromine atom, Z, R 2  and R 3  denote hydrogen atoms, R 4  denotes a --CH 3  radical and R 1  denotes a --CONH 2  group, namely the compound of the formula: ##STR39## having a melting point of 312° C. 
     
     
       21. A compound as claimed in claim 1, which corresponds to formula (I) in which Y denotes a bromine atom, Z, R 2  and R 3  denote hydrogen atoms, R 1  denotes --CH 2  CO 2  C 2  H 5 , and R 4  denotes either hydrogen or a methyl radical, namely: the compounds, respectively, of the formulae: ##STR40## having, respectively, a melting point of 181° C. and 104° C. 
     
     
       22. A compound as claimed in claim 1, which corresponds to formula (I) in which Y, Z and R 2  denote chlorine atoms, R 3  denotes hydrogen, R 4  denotes a --CH 3  radical, and R 1  denotes a CONHCH 3  group, namely: the compound of the formulae: ##STR41## having a melting point of 262° C. 
     
     
       23. A compound as claimed in claim 1, which corresponds to formula (I) in which Y denotes a bromine atom, Z and R 2  denote hydrogen atoms, R 1  denotes a --CN radical, and R 3  and R 4  are linked to one another to denote a --(CH 2 ) 2  --O--  (CH 2 ) 2  -radical, namely: the compound of the formula: ##STR42## having a melting point of 265° C. 
     
     
       24. A compound as claimed in claim 1, which corresponds to formula (I) in which Y denotes a bromine atom, Z, R 1 , and R 3  denote hydrogen atoms, R 2  denotes either a hydrogen atom or a bromine atom and R 4  denotes a ##STR43## namely: the compounds, respectively, of the formulae: ##STR44## having, respectively, a melting point of 164° C. and 143° C. 
     
     
       25. A compound as claimed in claim 1, which corresponds to formula (I) in which Y and R 2  denote bromine atoms, Z and R 1  denote hydrogen atoms, and R 3  and R 4  are linked to one another to denote a (CH 2 ) 5  -group, namely: the compound of the formulae: ##STR45## having a melting point of 72° C. 
     
     
       26. A compound as claimed in claim 1, in which Y, Z, R 1 , R 2  and R 3  denote hydrogen atoms and R 4  denotes a ##STR46## namely: the compound of the formulae: ##STR47## which compound is pasty. 
     
     
       27. A salt of a compound as claimed in claim 1, which results from the neutralization of a basic compound corresponding to formula (I) with a pharmaceutically acceptable. 
     
     
       28. A process of administering an antispasmodic, and uterine relaxant, a bronchodilator, a cardiac analeptic and/or composition, having an effective amount of active ingredient, to a human or other host in need of such therapy, wherein the active ingredient is a compound as claimed in claim 1 or a pharmaceutically-acceptable salt thereof. 
     
     
       29. A pharmaceutical antispasmodic, uterine, relaxant, bronchodilator, cardiac analeptic and/or sedative composition having an effective amount of a compound as claimed in claim 1 or of a pharmacologically-acceptable salt thereof in combination with pharmacologically-acceptable excipient. 
     
     
       30. A salt of claim 27 wherein the pharmaceutically-acceptable acid is a halogen hydracid, phosphoric acid, sulfuric acid, a carboxylic acid, isethionic acid or methanesulfonic acid.